Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease (PD). The regulation of neuroinflammation can reduce the severity of neurological damage to alleviate diseases. Numerous studies have shown that the phenotype switch of microglia is tightly associated with the nuclear factor κB (NF-κB)-mediated inflammatory pathway. Therefore, the small interfering RNA (siRNA) therapy for downregulating the expression of NF-κB, provides a promising therapeutic strategy for Parkinson’s disease treatments. Considering the brain delivery challenges of siRNA, a sequential targeting inflammation regulation (STIR) delivery system based on poly(amino acid)s is developed to improve the therapeutic effects of Parkinson’s disease treatments. The STIR system sequentially targets the blood–brain barrier and the microglia to enhance the effective concentration of siRNA in the targeted microglia. The results demonstrate that the STIR nanoparticles can transform microglial phenotypes and regulate brain inflammation, thus achieving neuronal recovery and abnormal aggregation of α-synuclein protein (α-syn) reduction in the treatment of Parkinson’s disease. Herein, this STIR delivery system provides a promising therapeutic platform in PD treatments and has great potential for other neurodegenerative diseases’ therapies.

Neurodegenerative diseases are characterized by progressive nervous system dysfunction, which affects over 90, 000 people every year. Although numerous contrast agents and therapeutic drugs are available for the diagnosis and therapy of neurodegenerative diseases, there are several limitations to their application. Particularly, these contrast agents and drugs are restricted from entering into the brain because of the blood-brain barrier, which represents a major bottleneck to efficacious and safe theranostics of neurodegenerative diseases. Nanoparticles can offer impressive improvement in the theranostics of neurodegenerative diseases, as they can effectively deliver contrast agents and drugs to target sites in the central nervous system. In this review, we describe various delivery systems, including lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles, and exosomes useful for the theranostics of neurodegenerative diseases. Finally, we outline current challenges and our perspectives on the development of delivery systems for theranostics of neurodegenerative diseases.